I037 Impaired beta-adrenoceptor-mediated-vasorelaxation to celiprolol is improved by candesartan cilexetil treatment in spontaneously hypertensive rats

Abstract

Celiprolol, a beta-blocker of third generation, is known to induce beta2-adrenoceptors (-AR) -mediated vasodilation, but the role of other beta-AR subtypes has not been investigated. Thus, the first purpose of this study was to evaluate the participation of beta3-AR in the celiprolol-induced relaxation in Wistar Kyoto rat (WKY) thoracic aorta. Furthermore, the second objective was designed to determine whether the celiprolol-induced relaxation was altered in spontaneously hypertensive rat (SHR) aorta, and to evaluate the effect of systemic or local angiotensin II (AngII) AT1 receptor (AT1R) antagonism on the relaxant effect of celiprolol. Aortic rings were mounted in organ baths and preconstricted with phenylephrine. Cumulative concentration response curves to celiprolol (0.1 to 300 μm) were established in different experimental conditions. Celiprolol produced a significant concentration dependent relaxation in WKY aorta (Emax=66.85±5.4 %, n=10) which was decreased in the presence of nadolol (beta1/beta2-AR antagonist, 10 μm) or SR59230A (beta3-AR antagonist, 1 μm). Relaxation to celiprolol was greatly decreased in denuded aortic rings, and abolished in intact rings pre-treated with L-Name (NOsynthases inhibitor, 100 μm). In SHR aorta, celiprolol-induced relaxation was significantly reduced (Emax=39.4±4.1 %, n=8) compared to WKY, whereas endothelium removal did not alter celiprolol-induced vasorelaxation. A 12 days treatment with candesartan cilexetil (AngII AT1R antagonist, 0.37 or 1 mg/kg/day) reduced systolic blood pressure (SBP) in both WKY and SHR, and significantly improved aorta relaxation to celiprolol more in SHR than in WKY (WKY : Emax=71.7±5,1 %, n=12 ; SHR : Emax=64.2±3.9 %, n=14). Furthermore, local aortic AT1R antagonism with candesartan CV11974 (100 mM) improved celiprolol-induced relaxation, but only in WKY aorta (Emax=78±5.6 %, n=7). Celiprolol induced an endothelial beta1-, beta2-and beta3-AR relaxation in WKY aorta through NO pathway. In SHR aorta, we showed, for the first time, that the celiprolol-induced vasorelaxation was impaired and that only the systemic AT1R antagonism with candesartan cilexetil improved the celiprolol-induced relaxation. This indicated that the beneficial effect of candesartan cilexetil was likely related to decreased SBP but not to specific mechanisms that may occur in aortic smooth muscle and/or endothelial cells.